Project Summary: Women who develop preeclampsia during pregnancy are at increased risk for subsequent atherosclerotic cardiovascular disease (ASCVD), but the biological mechanisms that mediate this risk have not been elucidated. Whether preeclampsia initiates unique pathophysiologic processes that lead to ASCVD, or exacerbates an underlying vulnerable vascular state, it provides a unique opportunity to identify women at increased risk for later ASCVD, and to provide insights into causal pathways and potential therapeutic targets. We propose that high dimensional biomarker signatures of preeclampsia will be evident across a woman's life-course, and will be associated with cardiovascular abnormalities: from pregnancy, through the immediate and late postpartum periods, to many decades later in women who develop ASCVD. We propose to leverage three large, well- characterized, ongoing cohorts of women (the Stanford March of Dimes study of pregnancy, the Danish National Biobank, and the Women's Health Initiative), and to apply cutting edge methods to gather and analyze high dimensional ?omics? data, and ultimately define novel pathophysiologic links between preeclampsia and ASCVD across the life-course. We will define biomarker signatures of preeclampsia during pregnancy and early post-partum, based on high dimensional measurements of the proteome, metabolome, transcriptome, and key cellular components, analyzed using novel computational methods, and determine their association with cardiovascular abnormalities (Aim 1); assess preeclampsia biomarker signatures, and their association with subclinical cardiovascular disease (endothelial dysfunction), five to twenty years after preeclampsia in women free of clinically evident ASCVD (Aim 2); and identify and validate a preeclampsia biomarker signature that is associated with development of clinically evident ASCVD (myocardial infarction, ischemic stroke, or revascularization of the coronary or carotid arteries) in later life (Aim 3). Finally, we will integrate the data across the life-course to define the evolution of preeclampsia biomarker signatures and their association with cardiovascular disease, to gain insight into causal pathways, and guide preventive and therapeutic strategies to reduce the excess risk of ASCVD associated with preeclampsia (Aim 4). 1